The overall goal of this Program Project is to increase our understanding of the contribution of estrogen to the development of breast cancer. We will address the use of breast cancer risk determinants in both African American and Caucasian women using a genetic, as well as a biochemical approach. We will address the issue of breast cancer risk determinants in both African American and Caucasian women using a genetic, as well as a biochemical approach. We also will evaluate the clinical utility of modifying breast epithelial exposure to estrogen by assessing the response of women at increased risk to the Selective Estrogen Receptor Modifier (SERM) Tamoxifen in two inter-related clinical trials. Thus the overall goals of the project are: 1) To develop a genetic model of breast cancer risk by analyzing a panel of proposed breast cancer susceptibility alleles related to hormone metabolism and response to DNA damage in African American and Caucasian women with breast cancer and a matched set of controls; 2) To develop a biochemical model of breast cancer risk by analyzing interindividual variability in estrogen metabolism in African American and Caucasian women with breast cancer and a matched set of controls, all of whom have been genotyped for the susceptibility alleles related to hormone metabolism; 3) To develop a pharmacogenetic model of breast cancer risk by combining genotypic data on the proposed breast cancer susceptibility alleles with the biochemical risk profile developed by studying estrogen metabolism in cases vs. controls; 4) To evaluate the response of MRI-defined alteration in breast volume as endpoints; 5) To identify biologic markers of response to Tamoxifen using markers of oxidative damage in peripheral blood and immunohistochemical evaluation of regions of increased density seen with MRI. At the conclusion of this study, we will have developed a comprehensive model for breast cancer risk based on a range of measures of estrogen effect that is applicable to both African Americans and Caucasians and we will have tested the ability of Tamoxifen to alter surrogate measures of risk. In addition, we will have evaluated the ability of Tamoxifen to alter surrogate measures of risk. In addition, we will have evaluated the potential of MRI-detected breast changes as surrogate endpoints and accumulated data on a range of histopathologic lesions that may be used as surrogate endpoints as well.